Method for the the formation of ibuprofen crystals

ABSTRACT

The present invention relates to a process for the formation of profen crystals, which comprises carrying out the formation of solids by displacement precipitation, cooling crystallization, evaporative crystallization or a combination thereof in the presence of one or more additives, and the use of the profens thus prepared for pharmaceutical formulations.

The present invention relates to a process for the formation of profencrystals, and to the use of the profens thus prepared for pharmaceuticaladministration forms.

As hydrophobic acidic active compounds, the analgesics of the groupconsisting of the profens are poorly water-soluble substances. Thisapplies in particular in weakly acidic and acidic pH ranges. Thus thelow rate of dissolution is the bioavailability-limiting step.

Profens have poor flow properties (strongly cohesive behavior) and poortabletability (strong adhesion to the die tools and poor plasticdeformability). These properties lead to tablets or pressings having lowstrengths, such that for the equalization of the unsatisfactorypharmaceutical properties in tablet recipes a high proportion ofexcipient (about 30-40%) is usually necessary, which leads to relativelylarge tablets and also to an increase in the production costs. Usually,a time-consuming and expensive moist granulation is necessary.

Numerous demands are made on pharmaceutical preparations, such as, forexample, tablets, coated tablets or alternatively preparations incapsules, on the part of the manufacturer, the patients, but also thecost bearer in the health service:

-   -   In order to facilitate taking by the patient and thus to        increase acceptance by the patient (=patient compliance),        tablets should be as small as possible. This means that an        optimum tablet recipe should contain a proportion of active        compound which is as high as possible.    -   On the other hand, as a result of the increase in the proportion        of active compound in a pharmaceutical preparation a more        economical production is possible as a result of savings in        excipients.    -   In order to be able to supply the active compound contained        efficiently to the body, the preparation should be designed such        that it has as high a bioavailability as possible. This means a        tablet should rapidly disintegrate in the gastrointestinal        tract, so that the active compound can rapidly dissolve.    -   Directly tabletable powders are therefore particularly        desirable, since the process of moist granulation and the cost-        and time-intensive drying step associated therewith can be        dropped here.    -   In order to make possible processability without special        industrial apparatus, the inactive excipients and the active        compound should have pharmaceutical properties which are as        ideal as possible. These are, for example: very good tableting        behavior, good flow behavior, no adhesive behavior (e.g.        sticking to die tools) and good dissolving behavior.

In the literature, numerous processes are described for improving thesolubility or the rate of dissolution of profens, e.g. the incorporationof ibuprofen into cyclodextrin inclusion compounds (EP 274 444, EP 490193) or the addition of surfactants (WO 99/17744 or U.S. Pat. No.5,141,961). The tableting properties (flowability/formation of pressingsof stable shape), however, are not improved by such processes. On thecontrary, as a result of these admixtures the resulting molded articlesare even more inconvenient for the patient to swallow on account of thesize owing to high proportions of excipient. For example, mostibuprofen-cyclodextrin inclusion compounds are complexes in the ratio1:1 (EP 274 44); a described ibuprofen-poloxamer complex consists of a4:6 mixture (WO 99/17744). In a therapeutically customary dose of200-400 mg of ibuprofen, tablets result by this means which can only beswallowed with extreme difficulty. In the therapy of rheumaticdisorders, even doses of 800 mg of ibuprofen are customary. Tablets of1.6-2.0 g, however, are no longer swallowable on account of their size.

Improvements in the rate of dissolution/solubility can be achieved bycrystallization of ibuprofen from different solvents (V. Labhasetwar etal., Studies on some crystalline forms of Ibuprofen, Drug Dev. Ind.Pharm. 19(6), 631-641 (1993)). These are different crystal forms,polymorphic forms of ibuprofen being reported because of the differentmelting points and IR spectra. The ibuprofen prepared according to theinvention is not a polymorphic form (identical melting point andidentical X-ray diffractograms as the present commercial product). Bymeans of the process according to the invention, improvements in thesubstance properties can moreover be obtained which have not beenachieved using the processes known hitherto.

A further reference confirms the better compressibility of ibuprofen, ifEudragits® (methacrylic polymers) are present in the crystallizationmedium in a displacement precipitation as a result of additions. Thecompressibility and the flow behavior compared with the starting productare markedly improved. By means of crystallization or precipitation by adisplacement precipitation using different solvents, however, ibuprofencontaining intercollated Eudragits® (spherical crystal agglomerates) wasproduced (precipitation of the Eudragits® on account of theirinsolubility under the conditions), so that here too a preformulatedpreparation and not pure ibuprofen is already present (K. Kachrimanis etal., Int. J. Pharm. 173 (1998) 61-74, J. Pharm. Sci. 89(2) (2000)250-259, S. T. P. Pharm. Sci. 10(5) 387-393 (2000)). The preparationsthus produced have a delayed release.

J. M. E. Bunyan et al., (Solvent effects on the Morphology of Ibuprofen,AIChe Symp. Ser. 87 (1991) 44-57) investigated the influences of varioussolvents on the morphology of ibuprofen. Using the generally knowncrystallization processes, it was possible to obtain an ibuprofen havingincreased bulk density and better compressibility. A marked increase inthe rate of dissolution, however, was not achieved. The rate ofdissolution hardly differs from commercially available ibuprofen andcorresponds to the profile “displacement precipitation” shown intable 1. For this also see the presentation of the rate of dissolutionin table 1. In this process seed crystals are generally employed, it notbeing clear, however, which crystal modification these seed crystalshave.

U.S. Pat. No. 4,476,248 discloses the crystallization of ibuprofen withthe aim of crystallizing cubic to spherical crystals having a relativelylarge crystal size and high bulk density. A cooling crystallization fromalcoholic solution without addition of additives is described. A markedincrease in the rate of dissolution is not obtained.

It is an object of the present invention to prepare rapidly soluble,readily flowable, readily compressible and tabletable profens of highpurity, which can be compressed directly to give tablets having goodpharmaceutical properties in high proportions of active compound inmixtures with only low proportions of customary pharmaceuticalexcipients without prior granulation.

We have found that this object is achieved according to the invention bya process for the formation of profen solids, which comprises carryingout the formation of solids in the presence of one or more additives.

It is likewise an object of the present invention to use the profenscrystallized in this way for the production of pharmaceuticaladministration forms.

The process according to the invention yields pure profen which

-   -   complies with the purity criteria of the leading and recognized        pharmacopeia worldwide    -   is free-flowing    -   exhibits an easy compressibility to give tablets    -   on compression has no sticking properties to the tablet die    -   in the production of pharmaceutically customary tablets, has to        be mixed with only extremely small amounts of nonactive        pharmaceutical excipients    -   does not, as in the case of profen, customarily have to be        subjected to a granulation process and dry- or moist-granulated        before tableting    -   can thus be employed in “direct tableting processes” during        tablet production    -   dissolves rapidly as the pure substance and from pharmaceutical        formulations with only small proportions of pharmaceutical        excipients in a manner not known hitherto (table 1 and table 4).

The tabletability can be markedly improved by the use of the profensprepared according to the invention. Merely by physical admixture ofsmall percentages (below 10%) of customary pharmaceutical excipients,without further process steps tablets can be directly pressed whosephysical properties such as press force/hardness ratio, friability,proportions of active compound and release rate of the active compoundare markedly superior to the tablets known hitherto and the tabletsdescribed in the literature.

This is achieved by addition of water-soluble and/or water-insolubleadditives during the crystallization. The choice of suitable solvents orsolvent combinations also plays a crucial role in this. The addition ofadditives on their own or in combination with suitable solvents leads toan unexpected and surprisingly markedly positive influence both on therate of dissolution and the flow and tableting properties. The additivesadded are no longer contained in the final product after formation ofsolids and separation have taken place or can be removed almostcompletely using simple washing processes. The additive accordinglycauses the development of a specific crystal habit having a specificsurface area, which decisively influences the substance properties. Byalteration of crystal crop/crystal habit or the crystal surface area,improvements in the critical substance properties are achieved, theincrease in the rate of dissolution and the improvement in the flow andtableting properties being to the fore. This process leads to a profenraw material which is suitable for direct tableting on simple physicaladmixture of only small proportions of pharmaceutical excipients (below10%) without granulation.

On account of the unfavorable physicochemical properties of the profens,the demands mentioned are usually not achievable in a conventional way.Owing to these unfavorable substance properties, a more cost-intensivepreparation process must be chosen—and even by means of this abiopharmaceutically optimum administration form is usually notrealizable. When processing poorly soluble pharmaceuticals, highproportions of excipients, such as disintegrants, usually have to beemployed. In order to improve the tabletability, as a rule higherproportions of binders, flow regulators and mold-release agents arenecessary.

It was found that the physicochemical properties of the profens can beinfluenced, not only by changes in the habit—as described above—butmoreover positively, by the formation of solids with additives. Thus inthe production of tablets from ibuprofen produced according to theinvention, for example, the addition of flow regulators, such as, forexample, of highly disperse silicic acid (Aerosil® 200) can also largelybe dispensed with. Such tablets also need only small amounts ofmold-release agents such as, for example, magnesium stearate or talcduring tableting. Because of the advantageous great hardnesses of thesetablets, the proportions of tablet binding agents are only very low, orthey can readily be dispensed with.

Thus an innovative method has been found to optimize the criticalsubstance properties of the profen raw materials without a highproportion of excipient being contained in the final product. The novelprofen is particularly suitable for the production of solidadministration forms, such as tablets, which contain a proportion ofactive compound of 80 to 98%, preferably 90 to 98%. However, it can alsobe filled directly into capsules without further processing because ofits good flow behavior and rapid rate of dissolution.

If needed, further active compounds can be added in the requiredconcentration to a (tablet) recipe produced using thehabit-/surface-modified profen presented here.

“Preparation” does not denote chemical synthesis here, but the stepsfollowing this of solids production and their recovery, modification andpurification.

“Tableting” means the compression of the “tableting mixture” (=activecompound+excipients) on a tablet press (eccentric or rotary press). In“direct tableting”, no granulation step takes place during production ofthe tableting mixture (neither moist granulation nor compaction). Thetableting mixture is accordingly produced by simple mixing of theconstituents (if appropriate after prior sieving).

The designation of the substance group consisting of the “profens”denotes active compounds containing the following structural element:

Representatives of this substance group are, for example, ibuprofen,naproxen, flurbiprofen, ketoprofen, flunoxaprofen, ibufenac, ibuproxam,pirprofen and loxoprofen, and their hydrates, solvates andphysiologically tolerable salts. The invention also relates to theoptically active forms, the racemates and the diastereomer mixtures ofthese compounds. Preferably, the process according to the invention forthe formation of ibuprofen crystals is employed.

Examples of physiologically utilizable salts are salts with amino acids,e.g. lysine. Further examples of such salts are alkali metal, alkalineearth metal, ammonium and alkylammonium salts.

Pure enantiomers of the profens are obtained either by resolution (viasalt formation with optically active bases) or by employing opticallyactive starting substances in the synthesis.

The term “pharmaceutical administration form” denotes tablets, coatedtablets (film-coated, lacquer-coated and sugar-coated tablets) andcapsules (filled with powder, granules or pellets). In this connection,the expression “pharmaceutical administration form” does not relateexclusively to the final product, but likewise to parts or intermediatesof one, such as, for example, a layer or multilayer tablet, parts of acapsule filling and the like.

Formation of solids is understood as meaning, for example, theproduction of crystals by displacement precipitation, crystallization bycooling the solution (cooling crystallization), evaporativecrystallization or alternatively spray drying.

The designation displacement precipitation describes a process in whichthe formation of solids of the active compound from a solution areproduced by addition of a nonsolvent. In this connection, the loweringof the temperature or the evaporation of solvent is additionallypossible. The precipitated active compound is recovered by filtrationand, if appropriate, by washing with a nonsolvent and subsequent drying.

During preparation of the crystals by cooling crystallization, thesubstance properties can be positively influenced by choice of asuitable solvent (preferably organic solvents, such as, for example,alcohols, e.g. isopropanol, if appropriate in a certain mixing ratiowith, for example, water). The designation cooling crystallizationdescribes a process in which the crystals of the active compound areproduced from a solution in the solvent by lowering the temperature. Theactive compound produced is recovered by filtration, washing, ifpossible, with a nonsolvent, filtration and subsequent drying.

A further route for crystallization is evaporative crystallization, inwhich the solvent is removed by vaporization or evaporation.

A combination of displacement precipitation, cooling crystallization orevaporative crystallization is moreover possible.

The designation “solvent” in this connection describes a liquid in whichthe active compound adequately dissolves, that is, for example, ethanol,methanol, propanol, isopropanol, acetone or acetonitrile.

The designation “nonsolvent” describes a liquid in which the activecompound has only low solubility, such as, for example, long-chainalcohols, but also water. The liquid thus serves as a precipitatingagent.

During preparation of the crystals by displacement precipitation, thesubstance properties can be positively influenced by choice of suitablesolvents (preferably organic solvents, such as, for example, alcohols,e.g. 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, ethanol,methanol or acetone, acetonitrile, propylene glycol, glycerol or DMF)and nonsolvents (such as, for example, water, aqueous solutions of acidsor organic solvents).

Preferably, those organic solvents are employed which form a miscibilitygap over a certain concentration range with the nonsolvent in thepresence of profens.

According to the novel process, profen crystallizate is formed byfirstly dissolving profen in a suitable solvent with addition ofadditive. Subsequently, the solvent is reduced, for example, by loweringthe temperature (cooling crystallization), by evaporation of the solvent(evaporation crystallization) or by addition of a suitable nonsolventand, if appropriate, of a second additive dissolved therein(displacement precipitation). A particularly readily flowable andtabletable and rapidly soluble solid results if solvent and nonsolventform a miscibility gap over a certain concentration range in thepresence of the profen and if the resulting crystals is given adequatetime for growth. Preferably, the formation of solids is carried out bydisplacement precipitation.

The formation of solids can be carried out either batchwise orcontinuously by cooling crystallization and/or evaporativecrystallization. The formation of solids by addition of a nonsolvent(displacement precipitation) is preferably carried out as a semi-batchprocess, the profen being introduced in the solvent and the nonsolventbeing metered in. By means of a suitable stirrer, a shear field which isas homogeneous as possible is produced using sufficiently high shearing(specific stirring power in the range from 0.2 to 2 W/kg, preferably 0.5to 1.5 W/kg). For this, multistage stirrers and/or stirrers withoutsharp edges (for example impeller stirrers) can be employed. Acombination of various types of stirrer is also sensible (for example animpeller stirrer in combination with axially transporting stirrerstages). The choice of an adequately long metering time for thenonsolvent is sensible (metering time between 30 min and 300 min,preferably between 40 and 210 min). The temperature is as a rule chosenin the range from 10° C. to 80° C., preferably in the range from 15° C.to 60° C., depending on the solvent. During the displacementprecipitation, the solution or suspension can simultaneously be cooledor some of the solvent can be evaporated.

As mentioned above, an improvement in the substance properties, interalia, is achieved in the presence of additives during the process of theformation of solids.

Suitable additives according to the invention are, for example, thefollowing surfactants

-   -   partial fatty acid esters of polyoxyethylene sorbitan, such as,        for example, polyethylene glycol(20)sorbitan monolaurate,        monopalmitate, monostearate, monooleate; polyethylene        glycol(20)sorbitan tristearate and trioleate;        polyoxyethylene(5)sorbitan monooleate;        polyoxyethylene(4)sorbitan monolaurate (also denoted as        polysorbate)    -   polyoxyethylene fatty alcohol ethers, such as, for example,        polyoxyethylene(4)lauryl ether, polyoxyethylene(23)lauryl ether,        polyoxyethylene(10)cetyl ether, polyoxyethylene(20)cetyl ether,        polyoxyethylene(10)stearyl ether, polyoxyethylene(20)stearyl        ether, polyoxyethylene(10)oleyl ether, polyoxyethylene(20)oleyl        ether (also denoted as macrogol fatty acid ether)    -   polyoxyethylene fatty acid esters, such as, for example,        polyoxyethylene stearate    -   ethoxylated triglycerides, such as polyoxyethylene glycerol        fatty acid esters, such as, for example, polyoxyethylene        glycerol monoisostearate,    -   polyoxypropylene-polyoxyethylene block polymers (poloxamers)    -   suger esters (such as, for example, sucrose monolaurate, sucrose        monopalmitate, sucrose monostearate, sucrose monomyristate,        sucrose monooleate)    -   sugar ethers    -   alkali metal soaps (fatty acid salts), such as, for example,        sodium laurate, palmitate, stearate, oleate    -   ionic and zwitterionic surfactants, e.g. betaines, such as, for        example, cocobetaine    -   phospholipids

The surfactants without a PEG chain in this case have particularimportance, such as especially the sugar esters and the fatty acid saltssucrose monolaurate being particularly preferably employed.

In order to achieve a removal from the final product which is asquantitative as possible, the HLB of the surfactants employed shouldbe >8 with water as a nonsolvent, since in the case of the morelipophilic surfactants a higher proportion of surfactant can remain inthe final product, which leads to increased agglomeration. Theobservation that surfactants which are present only during thepreparation of the pharmaceutical, but are then for the most partremoved by washing, permanently alter the pharmaceutical properties ofthe active compound is particularly surprising. An accelerated releaseby surfactants—in the case of their presence in the final product—islikely. Profen prepared according to the process presented herecontains, however, virtually no surfacant. Surprisingly, however, it wasnevertheless possible to detect an increase in the release rate due tothe novel process for the formation of solids. The formation of areadily flowable product on addition of surfactants is also surprising,since surfactants actually lead to an agglutination of the crystals—ifthey are contained in the final product. The addition of surfactants hasa decisive influence on the process of crystal formation and thus onhabit and surface area of the resulting product.

Possible additives are furthermore nonsurfactants. These are, forexample, the following:

-   -   sugars such as, for example, trehalose    -   dextrans (such as, for example, dextran 20, 60, 200)    -   polyvinyl alcohol, PVA    -   polyvinyl alcohol-polyethylene glycol graft copolymer (e.g.        Kollicoat® IR)    -   polyvinylpyrrolidone, povidone, PVP    -   hydroxyethyl starch, HES (such as, for example, HES 130, 400)    -   cellulose ethers such as, for example, hydroxypropylcellulose        HPC or hydroxyethylcellulose, HEC

The additives can be dissolved or emulsified in the solvent or in thenonsolvent.

Even on addition of one of these additives, a marked increase in therelease rate (individual examples cf. table 1 and table 2) and animprovement in the flowability can be detected. The tabletability isalso improved; pressings which are more stable in shape are formed.Sticking to the die tools can no longer be observed. An improvement inthe flow and tableting properties can particularly be detected whenusing sugar esters, fatty acid salts and the nonsurfactants.

Thus nearly all critical substance properties of the profens can bepositively influenced by means of the preparation process according tothe invention—and the pharmaceutical further processing can thus besignificantly simplified, the rate of dissolution and as a consequenceof this also the bioavailability can be improved. The profens producedby the process according to the invention have an in vitro releasewithin 5 minutes (phosphate buffer pH 7.4 according to USP XXIV by meansof the paddle process at 100 rpm) of ≧70%, preferably of ≧90%. TABLE 1Release rate of ibuprofen prepared by displacement precipitation(isopropanol/water) Amount released [%] Time Commercial Solvent changewithout Additive: [min] article addition sucrose monolaurate 0 0.0 0.00.0 2 15.1 20.9 85.2 5 36.9 48.9 98.8 8 59.5 67.2 100.0 10 73.9 76.5100.0 15 98.0 94.3 100.0 20 99.0 100.0 100.0

TABLE 2 Release rate of ibuprofen prepared by cooling crystallization(isopropanol) Amount released [%] Commercial article Additive: sucrosemonolaurate 0 0.0 0.0 2 15.1 85.9 5 36.9 98.4 8 59.5 99.5 10 73.9 99.915 98.0 100.7 20 99.0 100.6

A further increase in the positive effects on the physicochemicalproperties of the active compound can be achieved by combination of anumber of additives. In this connection, both a number of surfactantsand a number of nonsurfactants and combinations thereof can be employed,where preferably the combination of an additive from the groupconsisting of the surfactants with an additive from the group consistingof the nonsurfactants, particularly preferably the combination of sugaresters/nonsurfactants, leads to a considerable increase in the rate ofdissolution. Preferably, a combination of sucrose monolaurate withdextran 200, trehalose, Kollicoat® IR (=polyethylene glycol/polyvinylalcohol graft polymer), hydroxyethyl starch, Povidon® orhydroxypropylcellulose or a combination of Tween®80 with, for example,dextran 200 is employed. The profens crystallized by the processaccording to the invention have an in vitro release (phosphate buffer pH7.4; USP XXIV) of ≧70%, preferably of ≧90% (table 3). TABLE 3Crystallization by displacement precipitation (additives: combination ofsugar esters + nonsurfactants) Amount released [%] after 2 minCommercial article 15.1 Sucrose monolaurate 85.2 Suc. monolaurate +dextran 200 100.4 Suc. monolaurate + trehalose 100.1 Suc. monolaurate +HPC 100.8 Suc. monolaurate + Kollicoat ® 97.8 IR Suc. monolaurate +Klucel ® LF 98.9

Using the active compound having modified pharmaceutical properties (tobe attributed to modifications in the surface and habit) prepared by theprocess described here, powder mixtures for direct tableting having aproportion of active compound of >90% can be prepared.

An example of a recipe is mentioned below which can be tabletted by thedirect tableting route without the aid of further auxiliary techniques:

-   -   active compound (>90%)

The mean particle size of the profen employed does not play a crucialrole; preferably it should have a mean particle size of 10 to 100 μm.

-   -   Dry binder (about 4%), such as, for example, microcrystalline        cellulose (Avicel®)    -   Disintegration aid (about 4%), such as, for example, crosslinked        sodium carboxymethylcellulose (AcDiSol®), starch derivatives,        crosslinked PVP    -   Flow regulators (0.2 to 0.5%), such as, for example, highly        disperse silica (Aerosil®). In most cases, an additional flow        regulator can be dispensed with because of the good flow        properties.    -   Lubricant (0.1 to 0.5%), such as, for example, magnesium        stearate, calcium stearate, stearic acid, derivatives of stearic        acid (e.g. Precirol®), talc, higher molecular weight        polyethylene glycols. On account of the low adhesiveness of the        profen prepared by this process, the proportion of lubricants        compared with conventional recipes can be markedly lowered and        serves primarily for lubricating the tablet press.

The proportions of excipient mentioned here relate to the part of theadministration form which contains the active compound. An optionallyadditionally applied coating, which usually serves to conceal the tasteof the very bitter active compound, is not taken into account.

One or more further active compounds can also be added to thepharmaceutical administration forms.

These active compounds can be, for example: pseudoephedrine, ephedrine,phenylpropanolamine, tripolidine, acetylcysteine, ambroxol, azelaicacid, dehydrocodeine, hydrocodone or coffeine. Salts of these compoundsare preferred, provided the active compound is not present as a solidcrystal form.

The proportion of the other active compound(s) in the pharmaceuticaladministration form can be between 0.5 and 70% of the proportion in % byweight of the profen, depending on the potency of the active compoundand the desired effect.

The following examples are intended to illustrate the invention ingreater detail, but without restricting it to these examples. Themeasurements of the release rate was carried out according to USP XXIV.

EXAMPLES

-   1. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. Precipitation is then carried out by addition of ice water    (450 ml/stirrer speed 50 rpm) during the course of 70 min. During    this process cooling to 10° C. takes place. The crystals are    recovered by filtration and dried in vacuo. A fine, relatively    loose, readily flowable product is formed, which is prone neither to    adhesion nor to cohesion. On determination of the powder dissolution    (pure active compound), a 100% release is seen after 15 minutes (in    phosphate buffer pH 7.4 USP XXIV), which corresponds to the    commercial article Ibuprofen50 BASF AG obtainable at present. A    significant increase in the release rate does not take place.-   2. 5 g of naproxen are dissolved in 100 ml of isopropanol at 40° C.    3.2 g of sucrose monolaurate are added as an additive. Precipitation    is then carried out by addition of ice water (450 ml/stirrer speed    200 rpm) during the course of 70 min. During this process cooling to    10° C. takes place. The crystals are recovered by filtration, washed    with ice water (3×50 ml) and dried in vacuo. A relatively loose    product is formed. On determination of the powder dissolution (pure    active compound), a 100% release is seen after 15 seconds (in    phosphate buffer pH 7.4 USP XXIV). The commercial article obtainable    at present dissolves only to 35% after 2 minutes under identical    conditions; a 100% dissolution is only achieved after >30 min.-   3. 5 g of naproxen are dissolved in 100 ml of isopropanol at 40° C.    8 g of Tween®80 are added as an additive. Precipitation is then    carried out by addition of ice water (450 ml/stirrer speed 200 rpm)    during the course of 70 min. During this process cooling to 10° C.    takes place. The crystals are recovered by filtration, washed with    ice water (3×50 ml) and dried in vacuo. A relatively loose product    is formed. On determination of the powder dissolution (pure active    compound), a 100% release is seen after 15 seconds (in phosphate    buffer pH 7.4 USP XXIV). The commercial article obtainable at    present dissolves only to 35% after 2 minutes under identical    conditions; a 100% dissolution is only achieved after >30 min.-   4. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. 3 g of sucrose monolaurate are added as an additive.    Precipitation is then carried out by addition of ice water (450    ml/stirrer speed 200 rpm) during the course of 70 min; during this    process, cooling to 10° C. takes place; the crystals are recovered    by filtration, washed with ice water (3×150 ml) and dried in vacuo.    A fine, relatively loose, readily flowable product is formed, which    is prone neither to adhesion nor to cohesion. On determination of    the powder dissolution (pure active compound) a 100% release is seen    after 5 minutes (85% within 2 minutes) (in phosphate buffer pH 7.4    USP XXIV). The commercial article obtainable at present dissolves    only to <20% after 2 minutes under identical conditions; a 100%    dissolution is only achieved after >15 min.

5. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at 40° C. 3g of sucrose monolaurate are added as an additive. Precipitation is thencarried out by addition of ice water (450 ml/stirrer speed 200 rpm)during the course of 70 min; during this process, cooling to 10° C.takes place. The crystals are recovered by filtration, washed with icewater (3×150 ml) and dried in vacuo. 3 g of the product are washed againwith water (10×50 ml). A fine, relatively loose, readily flowableproduct is formed, which is prone neither to adhesion nor to cohesion.On determination of the powder dissolution (pure active compound), a100% release is seen after 5 minutes (85% up to minute 2) (in phosphatebuffer pH 7.4 USP XXIV). The commercial article obtainable at presentdissolves only to <20% after 2 minutes under identical conditions; a100% dissolution is only achieved after >15 min.

-   6. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. 1.0 g of sucrose monolaurate is added as an additive.    Precipitation is then carried out by addition of ice water (450    ml/stirrer speed 200 rpm) during the course of 70 min; during this    process, cooling to 10° C. takes place. The crystals are recovered    by filtration, washed with ice water (3×150 ml) and dried in vacuo.    A fine, relatively loose, readily flowable product is formed, which    is prone neither to adhesion nor to cohesion. On determination of    the powder dissolution (pure active compound) a 100% release is seen    after 5 minutes (85% within 2 minutes) (in phosphate buffer pH 7.4    USP XXIV).-   7. 45 g of ibuprofen are dissolved in 100 ml of isopropanol at    20° C. 1.5 g of sucrose monolaurate are added as an additive.    Precipitation is then carried out by addition of water (450    ml/stirrer speed 200 rpm) during the course of 70 min. The crystals    are recovered by filtration, washed with ice water (3×150 ml) and    dried in vacuo. A fine, relatively loose, readily flowable product    is formed, which is prone neither to adhesion nor to cohesion. On    determination of the powder dissolution (pure active compound) a    100% release is seen after 5 minutes (85% within 2 minutes) (in    phosphate buffer pH 7.4 USP XXIV).-   8. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. 3 g of sucrose monolaurate are added as an additive.    Precipitation is then carried out by addition of ice water (450 ml),    to which 8 g of dextran 200 are added (70 min). During this process,    cooling to 10° C. takes place. The crystals are recovered by    filtration, washed with ice water (3×150 ml) and dried in vacuo. A    fine, relatively loose, readily flowable product is formed, which is    prone neither to adhesion nor to cohesion. On determination of the    powder dissolution (pure active compound) a 100% release is seen    after <30 seconds (in phosphate buffer pH 7.4 USP XXIV). The    commercial article obtainable at present dissolves only to <20%    after 2 minutes under identical conditions; a 100% dissolution is    only achieved after >15 min.-   9. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. Precipitation is then carried out by addition of ice water    (450 ml/stirrer speed 200 rpm) during the course of 70 min. 3 g of    sucrose monolaurate and 8 g of trehalose are employed as additives.    During this process, cooling to 10° C. takes place. The crystals are    recovered by filtration, washed with ice water (3×150 ml) and dried    in vacuo. A fine, relatively loose, readily flowable product is    formed, which is prone neither to adhesion nor to cohesion. On    determination of the powder dissolution (pure active compound) a    100% release is seen after <30 seconds (in phosphate buffer pH 7.4    USP XXIV). The commercial article obtainable at present dissolves    only to <20% after 2 minutes under identical conditions; a 100%    dissolution is only achieved after >15 min.-   10. 80 g of ibuprofen are dissolved in 100 ml of isopropanol at    40° C. 3 g of sucrose monolaurate are added as additives.    Precipitation is then carried out by addition of ice water with 8 g    of hydroxypropylcellulose (Klucel®LF) (450 ml/stirrer speed 200 rpm)    during the course of 70 min; during this process, cooling to 10° C.    takes place. The crystals are recovered by filtration, washed with    ice water (3×150 ml) and dried in vacuo. A fine, relatively loose,    readily flowable product is formed, which is prone neither to    adhesion nor to cohesion. On determination of the powder dissolution    (pure active compound) a 100% release is seen after <30 seconds (in    phosphate buffer pH 7.4 USP XXIV). The commercial article obtainable    at this time dissolves only to <20% after 2 minutes under identical    conditions; a 100% dissolution is only achieved after >15 min.-   11. In a stirring vessel operated batchwise, ibuprofen was    precipitated on the 3 l scale from 2-propanol with water using    sucrose monolaurate and Klucel LF. A double-walled glass container    having three flow disrupters and a beveled blade turbine was    employed as the stirring element. A specific stirring power of 0.25    W/kg was introduced. 411 g of ibuprofen were introduced and    dissolved in 936 g of a solution of 2-propanol and sucrose    monolaurate (1.0% by weight of sucrose monolaurate in the solution).    3754 g of a 0.24% by weight water/Klucel LF solution were metered in    at 20° C. in the course of 10 min. The solid was separated off by    means of a suction filter and washed with water. A strongly    agglomerated crystallizate results, which is cohesive (poor    flowability). The solid nevertheless has a comparatively good rate    of dissolution. After 5 and 8 min respectively, 81 and 90%    respectively of the active compound are dissolved.-   12. In a stirring vessel operated batchwise, ibuprofen was    precipitated on the 3 l scale from 2-propanol with water using    sucrose monolaurate and Klucel LF. A double-walled glass container    having three flow disrupters and a beveled blade turbine was    employed as the stirring element. A specific stirring power of 1    W/kg was introduced. 414 g of ibuprofen were introduced and    dissolved in 943 g of a solution of 2-propanol and sucrose    monolaurate (1.0% by weight of sucrose monolaurate in the solution).    3780 g of a 0.24% by weight water/Kollicoat® IR solution were    metered in at 20° C. in the course of 70 min. The solid was    separated off by means of a suction filter and washed with water.    The crystallizate is very readily flowable and has a good rate of    dissolution. After 5 and 8 min respectively, 87 and 95% respectively    of the active compound are dissolved.-   13. In a 3 l stirring vessel, 357 g of ibuprofen were introduced and    dissolved in 643 g of a solution of 2-propanol and sucrose    monolaurate (1.2% by weight of sucrose monolaurate in the solution).    The stirring element used was a beveled blade turbine. The specific    power input by the stirrer was 1 W/kg. 3314g of a 0.97% by weight    water/Kollicoat® IR solution were metered in at 20° C. in the course    of 70 min. The solid was separated off by means of a suction filter    and washed with water. The crystallizate is very readily flowable    and has a good rate of dissolution. After 5 and 8 min respectively,    92 and 100% respectively of the active compound are dissolved.-   14. In a 3 l stirring vessel, 357 g of ibuprofen were introduced and    dissolved in 643 g of a solution of 2-propanol and sucrose    monolaurate (1.2% by weight of sucrose monolaurate in the solution).    The stirring element used was a beveled blade turbine (specific    power input: 1 W/kg). 3314g of a 0.97% by weight water/Kollicoat® IR    solution were metered in at 20° C. in the course of 120 min. The    solid was separated off by means of a suction filter and washed with    water. The crystallizate is very readily flowable and has a good    rate of dissolution.-   15. In a 3 l stirring vessel, 357 g of ibuprofen were introduced and    dissolved in 643 g of a solution of 2-propanol and sucrose    monolaurate (1.2% by weight of sucrose monolaurate in the solution).    The stirring element used was an impeller stirrer (specific power    input: 1 W/kg). 3314g of a 0.97% by weight water/Kollicoat® IR    solution were metered in at 20° C. in the course of 120 min. The    solid was separated off by means of a suction filter and washed with    water. The crystallizate is very readily flowable and has a good    rate of dissolution.-   16. In a 3 l stirring vessel, 357 g of ibuprofen were introduced and    dissolved in 643 g of a solution of 2-propanol and sucrose    monolaurate (1.2% by weight of sucrose monolaurate in the solution).    The stirring element used was an impeller stirrer (specific power    input: 0.15 W/kg). 3314g of a 0.97% by weight water/Kollicoat® IR    solution were metered in at 20° C. in the course of 120 min. The    solid was separated off by means of a suction filter and washed with    water. The crystallizate is more strongly agglomerated than the    solid from example 6.

17. The suitability for direct tableting is illustrated by the followingexample: 80 g of ibuprofen are dissolved in 100 ml of isopropanol at 40°C. 3 g of sucrose monolaurate are added as an additive. Precipitation isthen carried out by addition of ice water (450 ml/stirrer speed 200 rpm)during the course of 70 min; during this process cooling to 10° C. takesplace. The crystals are recovered by filtration, washed with ice water(3×150 ml) and dried in vacuo. A fine, relatively loose, readilyflowable product is formed, which is prone neither to adhesion nor tocohesion. A powder mixture for direct tableting results with thefollowing excipients: % by weight Ibuprofen 91.20 Avicel PH102 4.00AcDiSol 4.00 Aerosil 0.50 Mg stearate 0.30

The tablets pressed by direct tableting fulfill the requirements of Ph.Eur.; the maximum deviation on determination of the homogeneity of thematerial is 0.9%. The tablet surface is uniform. The ibuprofen preparedaccording to the invention is thus suitable for direct tableting (with ahigh active compound content of >90%). On account of the good flowproperties of the active compound, the proportion of Aerosil® can belowered further. A reduction in the proportion of lubricant (magnesiumstearate) is also possible.

On determination of the release behavior, a 100% release is seen after 2minutes (including the disintegration time of <30 sec) (in phosphatebuffer pH 7.4 USP XXIV).

Incorporation of the ibuprofen commercial article obtainable at presentinto the abovementioned tableting mixture produces tablets having severesurface defects, since strong adhesion (sticking) to the die tools takesplace. This ibuprofen is not suitable for direct tableting (at a highactive compound content of >90%). On determination of the releasebehavior a 100% release is seen after 10 minutes (including thedisintegration time of <30 sec) (in phosphate buffer pH 7.4 USP XXIV).In table 4, the release rates of tablets (ibuprofen commercialarticle/ibuprofen solvent change with sucrose monolaurate (4%, based onibuprofen)/ibuprofen solvent change with sucrose monolaurate and dextran200 (4 or 10%, based on ibuprofen)) are shown comparatively. TABLE 4Overview of the release rate from tablet formulations Amount released[%] Displacement Displacement Precipitation with precipitation additive:Commercial with additive: suc. monolaurate + Time article sucrosemonolaurate dextran 200 Minute 2 41.3 79.5 92.8 Minute 5 69.3 99.7 100.6Minute 10 100.1 100.8 100.1

-   18. 80 g of ibuprofen are dissolved in 100 ml of 90% strength    isopropanol (10% double-distilled water) at 40° C. 1.2 g of sucrose    monolaurate are added as an additive. Crystallization is then    initiated by cooling. To this end, the temperature is lowered to    15° C. in the course of 150 min and then to 0° C. in the course of    12 h. During this process, stirring is carried out at a stirrer    speed of 50 rpm. The crystals are recovered by filtration, dried in    vacuo and then washed with deagglomeration using ice water    (3×150 ml) and dried again in vacuo. A fine, relatively loose,    readily flowable product is formed, which is prone neither to    adhesion nor to cohesion. On determination of the powder dissolution    (pure active compound) a 100% release is seen after approximately 5    min (in phosphate buffer pH 7.4 USP XXIV). The commercial article    obtainable at present dissolves only to <20% after 2 minutes under    identical conditions; a 100% dissolution is achieved only after >15    min.

1. A process for the formation of ibuprofen solids wherein one or moreadditives are used in the solids formation process, wherein theibuprofen is dissolved in a suitable solvent while additives are added,wherein the additions used are a sugar ester, sugar, dextrans, povidone,polyvinyl alcohol-polyethylene glycol graft copolymers or combinationsthereof and the additives used are after solids formation and removalhave taken place no longer present in the end product or can be removedby washing, wherein the average size of the ibuprofen particles is inthe range from 10 to 100 μm.
 2. A process as claimed in claim 1, whereinthe formation of solids is carried out by displacement precipitation. 3.A process as claimed in claim 2, wherein the process is carried out as asemibatch process.
 4. A process as claimed in claim 1, wherein theformation of solids is carried out as a cooling crystallization.
 5. Aprocess as claimed in claim 1, wherein the formation of solids iscarried out by combination of a displacement precipitation with acooling crystallization.
 6. A process as claimed in one of claims 1 to5, wherein, as additives, a combination of sucrose monolaurate withdextran 200, Trehalose, Povidon or a polyvinyl alcohol-polyoxyethylenegraft copolymer is employed.
 7. A process as claimed in either of claims2 or 3, wherein the solvent used and the nonsolvent form a miscibilitygap over one part of the concentration range in the presence of profen.8. A process as claimed in one of claims 1 to 7, wherein at least onestirrer having a specific stirring power of 0.2 to 2 W/kg is employed inthe process.
 9. A process as claimed in one of claims 2, 3 or 7, whereinthe metering time for the nonsolvent is between 30 and 300 min.